The present invention is a continuation of ongoing research conducted by the Cancer Research Institute ("CRI") at Arizona State University, Tempe, Ariz. The essential thrust of the research at the CRI has been to source, isolate, elucidate and ultimately synthesize new compounds from marine sources which during their evolution have exhibited an innate ability to avoid/resist carcinoma disease.
As that project evolved, CRI devised a system of naming the new compounds using, in most part, the organism in which the new compound was first detected and from which the compound was extracted. Additional compounds are added to a series by the addition of an ascending cardinal number to the root word. Specific nomenclature is adopted because of a common source or because, when a multiple source is discovered, because of generic structural kinship to a previously named substance.
Thus, in the present invention, the novel compound disclosed herein is denominated "Halistatin 3" even though it is extracted from Phakellia sp. because it is more closely related to previously discovered Halistatins than it is to the Phakellistatins.
Thus, several compounds which may be useful in the treatment of one or more neoplastic diseases through chemotherapy have already been isolated from the Western Pacific Ocean marine sponge Phakellia sp. These compounds include the cyclic heptapeptide previously denominated as phakellistatin 4, and several decapeptides.
A great number of ancient marine invertebrate species in the Phyla Bryozoa, Mollusca and Porifera were well established in the earth's oceans over one billion years ago. Certainly such organisms had explored trillions of biosynthetic reactions in their evolutionary chemistry to reach present levels of cellular organization, regulation and defense. Marine sponges have changed minimally in their physical appearance during nearly 500 million years, suggesting a very effective chemical evolution in response to changing environmental conditions for at least the time period under consideration. Some recognition of the potential for utilizing biologically potent marine animal constituents was recorded in Egypt about 2,700 B.C., and by 200 B.C. sea hare extracts were being used in Greece for medicinal purposes. Such considerations, combined with the general observation that marine organisms (especially invertebrates and sharks) rarely develop cancer, led to the first systematic investigation of marine animal and plant anticancer constituents.
By 1968 ample evidence had been obtained, based on the U.S. National Cancer Institute's key experimental cancer systems, that certain marine organisms would provide new and structurally novel antineoplastic and/or cytotoxic agents. Analogous considerations suggested that marine organisms could also provide effective new drugs for other severe medical challenges, such as viral diseases. Furthermore, marine organisms were expected to contain potentially useful drug candidates (and biochemical probes) of unprecedented structural types, that would have eluded discovery by contemporary techniques of medicinal chemistry. Fortunately, some of these expectations have been realized in the intervening period. Illustrative of these successes are the discoveries of the bryostatins, dolastatins, and cephalostatins by the Cancer Research Institute at Ariz. State University, Tempe, Arizona where five members of these remarkable anticancer drug candidates are either now in human clinical trial or preclinical development.
As is well known to those presently engaged in medical research, the time between the isolation of a promising new compound and its availability in the market place takes several years in the best case and can take several decades when an entity to finance the tortuous regulatory trail is slow to appear. Consequently, industry, in association with the government, has devised a number of qualifying tests which serve two purposes. One purpose is to eliminate those substances whose results in the qualifiers unequivocally demonstrate that the further expenditure of funds on developing those substances would be economically counterproductive. The second, and more important purpose, is to identify those substances which demonstrate a high likelihood of success and therefore warrant the requisite further investment necessary to obtain the data which is required to meet the various regulatory requirements imposed by those governments which regulate the market place into which such substances will enter.
The present cost of obtaining such corroborative data approaches Ten Million Dollars ($10,000,000 U.S.) per substance. Basic economics dictate that such an investment will not be made unless there is a reasonable opportunity to recover it. This opportunity can only be provided through patent protection. Absent such protection, there will be no incentive and hence no investment, and the advances in such life saving drugs will stop.
Only two hundred years ago, many diseases ravaged humankind. Many of these diseases have been controlled or eradicated. In the development of the means to treat or control these diseases, work with the appropriate common experimental animals was of critical importance. With the various types of cancers, and with the HIV virus, such work is presently ongoing. The research for the treatment of various types of cancer is coordinated in the United States by the National Cancer Institute (NCI). NCI, as a government entity, has been charged with assisting all anti-cancer research. To establish whether a substance has anti-cancer activity, NCI has established a variety of protocols, one of which involves testing the candidate substance against a cell line panel containing 60 human tumor cell lines. This protocol has been verified, and is generally accepted throughout the scientific community. This protocol and the established statistical means of evaluating the results obtained therefrom, have been fully described in the literature (See e.g., Principles& Practice of Oncology, PPO Updates, Volume 3, Number 10, October 1989, by Michael R. Boyd, M.D., Ph.D.) which is incorporated herein by this reference thereto. The statistical analysis of the values obtained is explained in "Display and Analysis of Patterns of Differential Activity of Drugs Against Human Tumor Cell Lines: Development of Means Graph and COMPARE Algorithm" Journal of the National Cancer Institute Reports Vol. 81, No. 14, Pg. 1088, Jul. 14, 1989, by K. D. Paull et al. which is likewise incorporated herein by this reference thereto. Neither will be repeated herein.
The Constitution of the United States (Art. 1, Sec. 8) authorizes Congress to establish the United States Patent and Trademark Office (USPTO) to promote scientific advancement. In order for this obligation to be fully met, the USPTO must accept current medical and scientific realities in the area of medical research in order to fulfill the obligations placed upon it by the Constitution of the United States.
The Framers of the Constitution meant to advance scientific advancement. Cells are alive. The impairment of human tumor cell growth is utility. The sole right obtained from the grant of a letters patent is that of preventing others from exploiting the subject matter of the patent. The recognition of antineoplastic activity as utility can aid research in the United States, and prevent the citizens of the United States from being held hostage by foreign governments or foreign corporations, if such research is no longer viable in the United States.
A major component of vigorous efforts for over two decades has been directed at marine sponge antineoplastic and/or cytotoxic biosynthetic products. A number of unusual polyether macrolides, peptides and heterocyclic compounds have been uncovered. These efforts included the now disclosed isolation and structural elucidation of a new polyether macrolide, herein denominated "Halistatin 3".